Monohydroxyphenyl carbinols

ABSTRACT

Monohydroxyphenyl carbinols with at least two halogen atoms in the molecule have been found as microbicides which are effective against various types of bacteria and fungi.

United States Patent 11 1 Schellenbaum et al.

1 MONOHYDROXYPHENYL CARBINOLS [75] Inventors: Max Schellenbaum, Muttenz;Max

Duennenberger, Frenkendorf; Fulvio Casagrande, Binningen, all ofSwitzerland [73] Assignee: Ciba-Geigy AG, Basel, Switzerland [22] Filed:July 20, 1971 1 Appl. No.: 164,446

[30] Foreign Application Priority Data July 23, 1970 Switzerland11172/70 [56] References Cited UNITED STATES PATENTS 2,709,704 5/1955Brown 260/618 B X [451 Apr. 22, 1975 2.798.088 7/1957 Ritter et al260/618 H X 2,895,871 7/1959 Entemann.... 260/618 B X 2,945,886 7/1960Brown 260/618 H X 3,479,294 11/1969 Weck 260/619 R OTHER PUBLICATIONSFaith et al., Jour. Amer. Chem. Soc., Vol. 77, (1955), pp. 543-547.

Arnett et a1., Jour. Amer. Chem. Soc., Vol. 87, (1965). p 1023-1031.

Primary Examinen-Bernard Helfin Attorney, Agent, or Firm-Frederick H.Rabin; Nestor W. Shust [57] ABSTRACT Monohydroxyphenyl carbinols with atleast two halogen atoms in the molecule have been found as microbicideswhich are effective against various types of bacteria and fungi.

8 Claims, No Drawings MONOHYDROXYPHENYL CARBINOLS This invention relatesto monohydroxyphenyl carbinols, their manufacture and use.

According to the present invention there are provided monohydroxyphenylcarbinols of the general formula OH X OH C R X l 1 12 where X ishalogen,

X X and X are each halogen or hydrogen, and

R is a straight or branched chain alkyl group of 1-8 carbon atoms, orcycloalkyl group of 3-8 carbon atoms or phenyl, unsubstituted orsubstituted by halogen and- /or alkyl of l2 carbon atoms, there being atleast 2 halogen atoms in the molecule.

These compounds possess microbicidal activity.

The hydroxyl group in formula I is preferably in 2- or 4- position. Themost important cycloalkyl groups are cyclopentyl and, especially,cyclohexyl.

The alkyl groups can be, for example, methyl, ethyl and all isomers ofpropyl, butyl, amyl, hexyl, heptyl and octyl. Halogen includes bromineand chlorine.

Formula I includes hydroxyphenyl carbinols of the formula wherein X, X Xand X have the meanings given above, and Y and Y, are each methyl,halogen or hydrogen. Y Y and Y, are each halogen or hydrogen, therebeing at least 2 halogen atoms in the formula, and the phenolic hydroxygroup being in the 2- or 4- position to the carbinol bridge,

as well as hydroxyphenyl alkyl carbinols of the formula Preferred alkylgroups have 3-7 carton atoms, these groups being preferably unbranched.

Particularly interesting microbicidal are those 2- hydroxyphenyl alkylcarbinols of formula 3 wherein X and X are the same and are chlorine orbromine, while X and X are hydrogen and Alk is n-butyl or n-amyl.Furthermore, of great particular interest are monohydroxybenzhydrols ofthe formula I I c &

X.% H 2 Y (4) I ry Ill/T wherein n is 2, 3 or 4, and m is l, 2 or 3, andn+m is 3, 4 or 5.

The most important 4-hydroxybenzhydrols are given by the formula whereinp and q are each 1, 2 or 3 and p q is 3 or 4. In order to manufacturethe monohydroxyphenyl carbinols of the invention, a ketone of theformula wherein X, X X X and R have the meanings given above is reduced.The compounds of formulae 2 to 6 can be made from ketones of the formulaand wherein the various symbols have the meanings given above, and thenumbers of substituents and position of the hydroxy group are as givenabove also.

As reducing agent, for example a hydride can be used, the reaction beingcarried out in a solvent medium inert to the hydride.

For this, sodium borohydride is used with advantage, generally 0.25 1mol per mol of the hydroxyphenyl ketone to be reduced, corresponding tol to 4 equivalents. Particularly good yields are obtained if a polarsolvent is used such as water, methanol, ethanol, isopropanol ordioxane, or mixtures of these solvents such as a water/methanol mix. Thehydroxyphenyl ketone to be reduced is generally subjected to reaction inthe form of a phenolate, i.e. in salt form, preferably an alkali saltsuch as the ammonium, potassium or, particularly the sodium salt.

The reaction temperature may vary for example between C and the boilingtemperature of the solvent used. The reaction time is correspondinglygenerally 20 to 1 hours.

Further reduction methods which can be used are reduction with zinc dustin alcoholic alkali hydroxide solution, for example potassium hydroxideor sodium hydroxide, and reduction by means of sodium amalgam inalcoholic solution or by means of aluminum isopropylate in isopropanolicsolution (the method of Meerwein-Ponndorf-Verlay).

Note should also be taken of the catalytic hydrogenation ofhydroxyphenyl ketones. to give the hydroxyphenyl carbinols of thepresent invention.

The hydroxyphenyl ketones used as starting products are known (seeBelgian Patent Specifications Nos. 753,533 and 753,534) or aremanufactured by methods known per se, for example from the correspondingbenzoic acid or alkane carboxylic acid phenyl esters by the Friesreaction (compare Baltzly et al. Journal of the American ChemicalSociety 77, 2522 (1955), L. F. and M. Fieser, Lehrbuch der organischenChemie 1954, page 728 or G. A. Olah, Friedel-Crafts and RelatedReactions 1964, page 499). The reaction can take place in the moltenstate or in the presence of an organic solvent medium, e.g.nitrobenzene. On heating the corresponding phenyl ester together withaluminium chloride there results the monohydroxybenzophenone ormonohydroxyphenylalkyl ketone.

Particularly surprising for the compounds according to the invention isthe broad spectrum of anti-bacterial activity, which for most of thecompounds extends both over the area of gram-positive and gram-negativebac teria. From an application point of view, the lack of smell and thecolourlessness of the compounds of the invention is of particular value.

The present invention includes quite generally the use of the compoundsaccording to the invention in pest combating. The use of theantimicrobial compounds is possible on a very wide basis, particularlyfor the protection of organic substrates against attack by destructiveand pathogenic micro organisms (including phytopathogenic ones). Theanti-microbial agents noted are also suitable both as a preserving agentand as a disinfectant for technical products of all types, for plantprotection, in farming, in veterinary medicines and in cosmetictechnology.

The monohydroxybenzhydrols according to the invention are thus used fortreating or protecting organic materials, particularly textiles, byimpregnating at least one of these compounds into the material to betreated or protected or by applying such to the surface of thematerials.

Among non-textile technical products which can be preserved with the aidof compounds according to the invention, the following examples shouldbe noted:

Glues, binding agents, coating agents, textile dressings and treatingagents, printing and colouring pastes and similar preparations on thebasis of organic and inorganic dyes or pigments, also those whichcontain in admixture casein or other organic compounds. Also wall andceiling coatings, e.g. such as have an albumen containing colour bindingagent, are protected by addition of a compound according to theinvention from attack by pests. Use for wood protection is likewisepossible.

In the cellulose and paper industry also, the compounds according to theinvention can be used as conservation agents, inter alia for preventingthe known slime formation generated by micro organism infestation in theapparatus and machinery used for papermaking.

Furthermore by combination of the monohydroxybenzyhydrols of theinvention with surface active agents, particularly washing active agentsit is possible to produce washing and cleaning agents with exceptionalanti-bacterial or anti-mycotic action. The compounds according to theinvention can, for example, be

blended into soaps or combined with soap-free washing agents or othersurface active materials, particularly non-ionic and cationic washingagents, or they can be combined together with mixtures of soaps andsoapfree washing materials, wherein in these combinations theiranti-microbial effectiveness is retained to the fullest degree. By theuse of aqueous preparations of such washing and cleaning agentscontaining monohydroxybenzhydrols according to the invention, textilematerials, for example, can be treated anti-microbially during washing,since the active agent is substantive to the textile material.

Cleaning agents which contain the compounds of the above noted formulaecan be used both in industrial and domestic use, also in foodstuffindustries e.g. dairies, breweries and slaughter houses. The presentcompounds can also be used as a component of preparations which are usedfor cleaning or disinfection.

The action of the monohydroxybenzhydrols accord ing to the invention canalso be used in conserving and disinfecting preparations for plasticsmaterials. In the use of plasticisers it is advantageous to add theantimicrobial addition to the plastics material dissolved or dispersedin the plasticiser. It is advisable to take pains to obtain as even aspossible a distribution in the plastics material. The plastics materialswith anti-microbial properties can be used for useful articles of alltypes in which an effectiveness against varied germs, e.g. bacteria andfungi, is desired, thus for example in foot mats, bath curtainings,seats, steps in swimming baths, wall coverings, etc. By incorporationinto suitable waxing and polishing compositions, suitable floor cleaningand furniture care materials with disinfectant action can be produced.

Furthermore the compounds according to the invention can be used for theconserving and disinfecting treatment of fibres and textiles, whereinthey can be applied to both natural and synthetic fibers and thereeffect a permanent action against harmful (and pathogenic) microorganisms, for example fungi and bacteria. The addition of thesecompounds can take place therein before simultaneously with or after thetreatment of these textiles with other materials e.g. printing or dyeingpastes, dressings, etc.

Textiles treated in this way also are protected against the generationof a sweaty smell as is generated by micro organisms.

Treatment can take place for example by impregnating or spraying withsolutions or suspensions containing the above noted compounds as activeagent. The active agent can vary according to the purpose of use between0.1 and 50 grams active substance per litre, preferably 1 grams.

Generally textile materials of both synthetic or natural origin can besatisfactorily protected against attack by mould fungi or bacteria by acontnt of from 0.1 to 3% of active agent. The active agent noted can beadded together with other textile treatment agents as dressing agents,permanent creasing treatments etc.

The ways of using the active agents of the present invention cancorrespond to the usual formulations for 5 pest control agents, forexample, agents which contain the said active agent can optionally alsocontain additives such as solvents, dispersing agents, wetting agents,adhesives, light protection agents, optical brighteners etc., togetherwith other pest control agents, such as fungicides and bactericides.Particularly, however, as well as the active agent according to theinvention, the agent can contain a further solid or liquid thinningagent or a solid or liquid carrier. The invention extends tomicrobicidal agents which contain compounds of the general formula I.

The following examples will serve to illustrate the invention.

EXAMPLE 1 the compounds of formula 30 OH OH which was an oil whichcrystallised on standing; melting point l20128C.

The purified compound from recrystallisation from chloroform melted at130-l3lc. The pure yield amounted to 7.3 g.

B. To 31 g aluminiumisopropylate in 150 ml isopropanol there was added asolution of 9.0 g Z-hydroxy- 5,3',4,trichlorobenzophenone in 25 mlisopropanol. The reaction mixture was then boiled under reflux for 20hours. After the addition of 150 ml Z-n-hydrochloric acid at 25C, theproduct was extracted with ethyl acetate and the extract washed firstwith saturated potassium bicarbonate solution and then with water. Fromthe extract which was dried over sodium sulphate there remained afterthe removal of the solvent 8.5 g of the compound 100 as an oil whichcrystallised on standing.

After recrystallisation from chloroform the compound was present in pureform and melted at 130l 31C.

In the same way as example 1 or according to one of the other methodsgiven above the following compounds can be prepared which are shown inthe follow ing table A:

TABLE A Com- R R, R R R R R, R R Melting point in poun No. C

OH H H Cl H H Cl Cl H 131 132 101 OH H H Cl H H Cl H H 102 104 102 OH HC1 H H H Cl H Cl 30 103 OH Cl H Cl H H C1 C1 H 155 157 104 OH H H Cl H HCl H Cl 110-112 105 OH C1 H Cl H H Cl H H 93 94 106 OH Cl H Cl H H Cl HCl 106 107 107 OH C1 H Cl Cl H Cl H C1 133 134 108 OH Cl H C1 Cl H Cl HH 176 178 109 OH H Cl H Cl H C1 Cl H 145 146 110 OH H Cl H H H C1 C1 H106 107 111 OH C1 H Cl Cl H Cl Cl H 189 190 1 12 OH H H C1 Cl H Cl Cl HOil 113 OH H H Br H H Cl C] H 134 135 114 OH Br H Br H H Cl Cl H 124 125115 OH H C] H C1 Cl Cl H H 135 136 116 OH H C1 Cl H C1 C1 H H 119- 117OH H H Br H C1 Cl H H 103 104 1 18 OH Br H Br H Cl Cl H H 278 279 119 OHH Cl H C1 C1 H Cl H 146 147 120 OH H Cl H H C1 H C1 H 135 136 121 OH ClH Cl Cl Cl H Cl H 156 157 122 OH H Cl Cl H Cl H Cl H 182 183 123 OH H C1H C1 C1 H H Cl 175 176 124 OH Cl H Cl C1 C1 H H C1 189 190 125 OH H ClCl H C1 H H Cl 156 157 126 OH H Cl Cl H H Cl H H 98- 99 127 OH H C1 H ClCH H H H 115- 116 I28 OH H C1 H H CH H H H 131 132 129 OH Cl H Cl Cl CHH H H 153 154 130 OH H Cl H C1 C1 H H H 99 100 131 OH H Cl H H Cl H H H1l4-115 132 OH H H Cl H Cl H H H 97- 98 133 OH Cl H Cl H C1 H H H 78 79134 OH Cl H Cl C1 C1 H H H 123 124 135 OH H Cl Cl H Cl H H H 109 110 136OH Cl H Cl H H H H H 94- 95 137 OH Cl H Cl C1 H H H H 168 169 138 OH BrH Br H H H H H 121-122 139 OH Cl H Cl Cl H CH H H 175 176 140 OH Cl H ClCl H Br H H 178 179 141 OH Br H Br H 'H Br H H 135 136 142 OH H H Br H HC1 H H 105 106 143 OH Br H Br H H C1 H H 116-117 144 H H OH C] H C1 C1 HH 144 145 145 H C1 OH Cl H H C1 H H 165 167 146 H Cl OH C1 H H C1 C1 H175 176 147 H Cl OH Cl H H Br H H 159 160 148 H C1 OH H Cl H C1 C1 H 147148 149 C1 H OH H H C1 C1 H H 159 160 150 H Cl OH H H H C1 C1 H 121 122151 H Cl OH C1 H H H H H 144 -145 152 H C1 OH Cl H C1 C1 H H 162 163 153H C1 OH CI H CH H H H 158 159 154 H Cl 0H CI H Cl H H H 139 140 H C1 OHH C1 C1 H H H 176 177 156 C1 H OH H Cl H C1 C1 H 197 198 EXAMPLE 2 OH 019 (209) CH -CH -CH -CH- fully. This was filtered off, washed with water,dried and recrystallised once from methylene chloridehexane forpurification; melting point 130131C. The Pure yield amounts to 5.2 g.

In similar fashion the compounds given in the following table B can beprepared. The general formula for compounds of table B is:

EXAMPLE 3 TABLE C-Continued Determination of the Minimum Inhibiting C dConcentration (MIC) Against Bacteria and Moulds by Dmpou" Mic ppm theGradient Plates Test Nos. (1) (2)-ll- 152 25 154 30 Gradient test 1 isgiven by W. Szybalsk1 et al., Sc1- 155 30 ence 116, 26 (1952). $3?Gradient plate test 2 is that given by Nuesch and 203 20 Knuesel,Sideromycins, in the book by Gottlieb and 204 60 Shaw, Antibiotics,Mechanism of Action, volume l 1 (1967), Springer Verlag. 207 30 Thecompounds of formulae 1 and 2 were mixed as 583 3 suitable formulations(eg as solutions in dimethylsulf- 210 oxide) of given concentration withwarm brain heart g3 infusion-agar (bacteria) or mycophil-agar (moulds).215 The liquid mixtures were poured onto a solid wedge- 216 10 shapedbase agar layer and likewise allowed to solidify. g The test organismwas then applied in a line perpen- 219 1 dicular to the gradient with apasteur pipette. After incubation for 24 hours at 37C (bacteria) or 72hours at 20 222 i 30C (moulds) the length of the bacteria which hadgrown on the inoculation line was measured and ex- 225 pressed in partsper million of active agent. The results 226 0,2 are given in thefollowing tables C to F.

TABLE C Minimu h'b t D t t' t Minimum inhibiting concentration against Egag 2 g Staphylococcus aureus (Bacteriostasis) Sc la col ac enos 3515Compound MIC in ppm Com ound MIC in ppm 8 101 20 101 30 102 20 I02 3 I0310 I03 2 I04 50 104 20 35 105 35 I05 3 106 40 I06 3 I 108 30 I07 05 109I5 108 0.5 110 20 109 0,25 111 20 H0 3 H2 25 111 1 40 113 30 112 2 11430 113 0,3 115 10 114 0,5 116 20 115 0,4 117 40 H6 2 H9 20 117 10 120 40118 0,2 45 122 15 H9 0,4 126 I0 I20 4 I27 40 121 0,1 128 50 I22 3 I30 20123 0,3 I31 70 124 0,3 133 60 125 4 50 I35 30 126 4 136 66 127 3 137 40128 20 I38 50 I29 3 I40 30 130 3 141 20 I3] 30 I42 40 132 50 55 143 30133 I0 149 50 134 3 I50 45 135 9 154 50 I36 30 I56 50 137 3 201 50 138I0 203 40 139 3,5 60 205 40 140 2 206 35 141 2 207 40 142 30 208 30 I432 209 30 144 20 213 30 I45 50 215 40 I46 20 65 216 20 147 25 217 20 14s6 21s 10 149 20 222 10 Minimum inhibiting concentration against TABLE EAspergillus niger (Fungistasis) Compound MlC in ppm TABLE F Minimuminhibiting concentration agamst 45 Trichophyton mentagrophytes(Fungistasis) Compound MlC in ppm TABLE F-Continued Compound MIC in ppmEXAMPLE 4 A specimen of 140 g cotton-poplin was impregnated at 20C for 7minutes in a bath of the following composition:

1000 ml water 2.7 ml cloth softening rinsing dye (containing 7% of amixture of di-octadecyl and di-hexadecyldimethyl-ammonium chloride) 15mg of the compound of formula (109) (added as a solution in 0.5 mldimethylsulfoxide) The so treated cloth specimen was squeezed out after100% dyebath take up and then dried at 45C.

For testing the action against bacteria, roundels of 20 mm diameter werecut from the impregnated cloth and laid on brain-heart infusion agarplates, which had been pre-infected with Staphylococcus aureus. Theplates were then incubated for 24 hours at 37C.

Two observations were made, that of the zone of inhibition arisingaround the roundels (inhibition zone in mm) and the determinable growthabove or below the cloth. The inhibition zone was only a trace quantitywhile the determinable growth was 0%.

Similar effects were obtained with further compounds of formula 1 or 2.

EXAMPLE 5 For the manufacture of an anti-microbial tablet of soap, 2.4 gof one of the compounds of Formula 1 or 2 were added to the followingmixture:

120 g natural soap in flake form 0.12 g disodium salt ofethylenediaminetetracetic acid (dihydrate) 0.24 g titanium dioxide.

The soap shavings obtained by rolling were powdered with a high speedmixture and then pressed to soap tablet form.

Concentrated aqueous solutions of the anti-microbial soaps were mixedinto warm brain heart infusion agar so that iii-corporation dilutionrose with 2, 10, 20, 100 etc. parts per million active agent wereproduced. The warm mixtures were poured into petri dishes, allowed tosolidify and then infected with Staphylococcus aureus.

After 24 hour incubation at 37C the minimum inhibiting concentration wasdetermined. The results are shown in the following table. Similarresults were obtained by the use of other compounds of formulae 1 and 2.

EXAMPLE 6 Specimens of 100 g cotton-cretonne were impregnated on thefoulard with 1% solutions of compounds of formula 1 in isopropanol at Cand then squeezed out with 100% bath take-up.

In the same way, samples of 100 g wool cheviot were treated.

The textiles which were dried at 30 to 40C contained 1% by weight ofactive agent taken on their own weight.

For testing the action against bacteria, roundels of 10 mm diameter cutfrom the impregnated cloth, dewatered and watered, were laid for 24hours at 29C on brain heart infusion agar plates which had beenpreviously infected with Staphylococcus aureus. The plates were thenincubated for 18 hours at 37C.

Two factors were observed: first, the inhibition zone (in mm) arisinground the roundels and second, the microscopically determinable growth(in under or on the cloth.

Results are expressed in the following table; similar results wereobtained also with further compounds of formulae 1 and 2 SubstantivityTests With Calf-Hide Roudels Calf-hide roudels of 10 mm diameter weredipped for termined in Results are as follows:

Soap with Compound No. Inhibition zone in- Growth in Similar values wereobtained using other compounds of formulae 1 and 2.

EXAMPLE 8 The following mixture was milled on the twin-roll mill at Cfor 20 minutes:

100.00 g polyvinylchloride 19.20 g di-( Z-ethyl-hexyLphthalate) 27.00 gdi-(2-ethyl-hexyl-sebacate) 1.50 g Ba/Cd-laurate 0.25 g Stearic acid7.80 g of a solution of 3.10 g of a compound of formula 1 in 4.70 gdi-(2-ethyl-hexyl-phthalate) The roll separation was adjusted so that 1mm thick sheets were formed which were then pressed for 20 minutes atl70C under a pressure of 1,400 kglcm For testing the action againstbacteria, discs of 10 mm diameter were stamped from the rolled softpolyvinylchloride sheet and laid on brain-heart infusion agar plateswhich had previously been infected with Staphyloccocus aureus. Theplates were then incubated for 24 hours at 37C.

The zone of inhibition arising round the discs was measured in mm andthe microscopically determinable growth above and below the softpolyvinylchloride was measured in The results are given in the followingtable: Similar action is observed with other compounds of formulae 1 and2.

wherein X is halogen; X X and X are each hydrogen or halogen; Y ishydrogen, halogen or methyl; and Y and Y are each hydrogen or halogen;and wherein at according to claim 1. least two of X X X Y, Y; and Y arenot hydrogen. 6. The compound 2. A compound according to claim 1 offormula wherein n is 2, 3, or 4, m is 1, 2 or 3 and n +m is 3,

The Compound according to claim 2.

01-3 01 7. The compound CI;

' c1 CH- on C1 OH I Cl 01 c1 Cl CH according to claim 2. 4. The compoundOH C1 C1 on I I I acc ordlng to claim 2. Cl 0 CH 7 Cl 8. The compound DI C1 C1 OH Cl according to claim 2. 0H

5. The compound I ,u Cl CH Ol-l Cl C1 I cl C H Cd 40 according to claim2. C1 C1 =1:

1. A COMPOUND OF THE FORMULA2-((Y,Y2,Y3-PHENYL)-CH(-OH)-),X,X1,X2,X3-PHENOL WHEREIN X IS HALOGEN;X1, X2 AND X3 ARE EACH HYDROGEN OR HALOGEN; Y IS HYDROGEN; AND WHEREINAT LEAST TWO OF X1, X2, EACH HYDROGEN OR HALOGEN; AND WHEREIN AT LEASTTWO OF X1, X2, X3, Y, Y2 AND Y3 ARE NOT HYDROGEN.
 1. A compound of theformula
 2. A compound according to claim 1 of formula
 3. The compound 4.The compound
 5. The compound
 6. The compound
 7. The compound